Viral-induced encephalitis remains a major cause of morbidity and mortality throughout the world. Effective therapies are available for only a few neurotropic viruses, and even when these infections are optimally treated, residual mortality and neurological sequelae remain considerable. No established treatment exists for flaviviruses, including West Nile virus, (WNV) the most common cause of epidemic encephalitis in the United States and Japanese encephalitis virus (JEV), the most common cause of viral encephalitis worldwide. Similarly, although treatment with acyclovir improves the outcome of herpes simplex type-1 (HSV-1) encephalitis, the most common acute sporadic encephalitis in the Western world, residual morbidity and mortality remain significant. Further, nearly half of all emerging viral diseases are associated with encephalitis or serious neurological clinical symptoms. Novel strategies for identifying and treating viral central nervous system (CNS) infections are thus urgently needed. OBJECTIVE 1. To identify specific cellular genes that are differentially regulated during virus-induced encephalitis and have potential as novel therapeutic targets for these diseases. Available data suggests that encephalitis induced by a variety of viruses is associated with the activation of similar cellular signaling pathways. We have previously performed microarray analysis to determine genes that are differentially regulated during reovirus-induced encephalitis. We now propose to perform microarray analysis of mRNA extracted from the brains of mice during HSV-1- and WNV-induced encephalitis and to identify alterations in cellular gene expression and cellular signaling pathways that are common all 3 viruses. These genes are expected to have a high likelihood of providing therapeutic targets for encephalitis induced by a variety of viruses. The applicability of using altered expression of these genes or activation of these pathways as therapeutic targets for virus-induced encephalitis will be further assessed by determining the expression of these genes and activation of these pathways in the brain following infection with other encephalitic viruses, including JEV, Sindbis virus (SINV), and Venezualen equine encephalitis virus (VEEV). OBJECTIVE 2. Evaluation of novel therapeutic targets for virus-induced encephalitis. The experiments proposed in specific aim 1 will identify cellular genes and signaling pathways that have potential as therapeutic targets for virus-induced encephalitis. We propose to evaluate these potential therapeutic targets by determining virus-induced pathogenesis using treatments designed to block expression of these genes and pathways. PUBLIC HEALTH RELEVANCE: Viral-induced encephalitis remains a major cause of morbidity and mortality throughout the world. The proposed studies will identify cellular genes and signaling pathways that are activated during virus-induced encephalitis. In addition, the proposed studies will evaluate the role of these genes and pathways as novel therapeutic targets for these diseases.